Treating Microalbuminuria—Cosmetic Exercises with Urine Chemistry or Effective Reduction of Clinical Events?
Authors: F.W. Asselbergs, G.F. Diercks, H.L. Hillege, A.J. van Boven, W.M. Janssen, A.A. Voors, D. de Zeeuw, P.E. de Jong, D.J. van Veldhuisen, W.H. van Gilst
Journal: Journal of the American Society of Nephrology (2005)

Recently there has been intense interest in the issue of microalbuminuria as reflected by a number of reviews and guidelines. Microalbuminuria was first described by diabetologists (1,2) as a predictor of cardiovascular and renal risk in diabetic patients (3–5). Today microalbuminuria has become a well established risk factor in nondiabetic subjects as well. Several observational studies established that in nondiabetic subjects microalbuminuria and even high normal albuminuria increase the risk of cardiovascular events and cardiovascular death (6–9). In some studies the risk increased parallel to increasing albumin excretion rates. In diabetic subjects it has been found that even albuminuria in the upper normal range caused a striking increase of cardiovascular risk (by a factor of 9.8) and renal risk (by a factor of 12.4) (10). Similarly, in nondiabetic individuals with normoalbuminuria as well, the results of the Heart Outcomes Prevention Evaluation (HOPE) Study (11) and the Losartan Intervention For Endpoint Reduction (LIFE) Study (12) show a progressive increase of cardiovascular end points when albuminuria is higher than the approximate population median. High normal albumin excretion rates in nondiabetic subjects are equally associated with a higher risk to develop frank microalbuminuria (13), just as they are in diabetic patients (10) In diabetic (14) as well as in nondiabetic patients with overt proteinuria it has been shown that treatment with blockers of the renin-angiotensin system diminishes the cardiovascular risk and that this goes in parallel with the reduction of proteinuria. What had not been shown so far was whether interventions reduce cardiovascular endpoints in individuals who have nothing but microalbuminuria as a risk factor. Clarification of this point would be of considerable interest to justify screening for albuminuria in nondiabetic patients. Asselbergs et al. selected an angiotensin-converting enzyme (ACE) inhibitor and a statin for intervention in such subjects, the latter particularly because, in the past, reduction of albuminuria during administration of statins had been seen in some (15,16) but not all studies. It is not easy to find a suitable cohort of patients for such a trial, but the PREVEND Study provided a unique opportunity for this endeavor. In the Dutch city of Groningen, 40,856 subjects (47.8% of the inhabitants) had sent in their morning urine. A subgroup of 1439 individuals with persistent urinary albumin concentration >10 mg/L in the morning urine, BP <160/100 mmHg, and total cholesterol <8 mmol/L was randomized to receive either the ACE inhibitor fosinopril (20 mg/d) or matching placebo on the one hand, or the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor pravastatin (40 mg/d) or matching placebo on the other hand. The mean duration of follow-up was 46 mo. This population was relatively healthy: Mean age 51 yr, mean systolic BP 130/76 mmHg, mean cholesterol 5.8 mmol/L, and only 3.4% had a history of a cardiovascular event. The median urinary albumin excretion was no more than 22.8 mg/24 h (range 15.8 to 41.3). The primary endpoint was the combined incidence of cardiovascular death or hospitalization for one (or several) of the following: Nonfatal myocardial infarction or myocardial ischemia, heart failure, peripheral vascular disease, cerebrovascular accident. The results are truly remarkable for a middle-aged population with albumin excretion in the upper normal or low microalbuminuric range, with a low prevalence of diabetes, relatively normal BP and cholesterol, as well as with few individuals having a history of cardiovascular events—and despite a sobering compliance (about 65% in this asymptomatic population). Fosinopril caused an extremely modest reduction of BP while pravastatin lowered LDL-cholesterol substantially from 4.0 to 3.8 mmol/L. As anticipated, fosinopril lowered urinary albumin from 23.5 to 17.6 mg/24 h while pravastatin, in contrast to previous reports (15,16), failed to do so. What about cardiovascular endpoints? Subjects receiving fosinopril had a 40% lower incidence of the primary cardiovascular endpoint compared with the placebo arm, i.e., 3.9% versus 6.5%, but P < 0.098. The reduction of cerebrovascular accidents was striking (0.2 versus 2.3% (P < 0.05). Subjects with urinary albumin in the highest quintile (>50 mg/d) had a significantly higher risk for developing a cardiovascular event on placebo than on fosinopril. The risk in this subgroup was reduced by fosinopril from 13% to 5.2%, reducing the relative risk by 60%. In contrast, pravastatin did not lower the incidence of the primary endpoint (−13%; P = 0.649). The data of this interventional trial are in line with observational data in the LIFE Study suggesting that reduction of albumin excretion is associated with a lower risk for the primary cardiovascular endpoint (17). What can we learn from this trial, which assessed a relatively small cohort with very low cardiovascular risk and urinary albumin values considerably lower than in previous studies? The HOPE Trial (18) and the Europa (EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease) trial (19) had shown that ACE inhibitors reduce cardiovascular endpoints in populations at high cardiovascular risk. Despite the biostatistical borderline significance, the results of the PREVEND IT study suggest that screening for urinary albumin concentrations in the high normal or microalbuminuric range will identify individuals at high cardiovascular risk who might benefit from treatment with an ACE inhibitor (but somewhat surprisingly not with a statin). Why is microalbuminuria such a powerful predictor? Although microalbuminuria is an independent predictor of risk, it is also associated with an array of other cardiovascular risk indicators, the metabolic syndrome (20), insulin resistance (21) and a high risk of de novo diabetes (22) which is reduced, however, by renin-angiotensin system blockade (23), high body mass index (24), evidence of oxidative stress (25), smoking (26), hypertension (27), and even developmental abnormalities of the kidney (“nephron underdosing”) (28). What is currently not well understood is the link between albuminuria and the cardiovascular risk, and this continues to be a fascinating challenge to nephrology. The time-honored Steno hypothesis ascribed the cardiovascular risk in microalbuminuric patients to microinflammation and endothelial dysfunction (29). There is indeed substantial evidence for this hypothesis in microalbuminuric patients (30). Recent findings of cross-talk between podocytes and endothelial cells in the glomerulus may provide a potential link between endothelial cell dysfunction and deranged glomerular permselectivity (31–33). Open questions remain. Apart from the obvious need to see the results confirmed in a larger prospective study, the following issues immediately come to one’s mind. Which is the best method for detecting urinary albumin in the kidney (34)? Which are the most appropriate cut-offs? In this age where economic aspects are of ever more importance in medicine we also need information on whether screening for albuminuria is cost-effective. We should also know the frequency of side effects in the long run and compliance problems. Even in the short run compliance was remarkably low in the disciplined but asymptomatic Dutch. Nevertheless, the study raises the hope that blockade of the renin-angiotensin system provides benefits beyond BP lowering (35), even in low-risk individuals presenting with nothing but urinary albumin values in the high normal or microalbuminuric range. The public health importance of this issue is obvious.